SUMMARY Hispanic children are more likely to develop acute lymphocytic leukemia (ALL), and when this occurs they are 39% more likely to die than non-Hispanic Whites. This disparity is due, in part, to a subtype of B-cell precursor ALL (B-ALL) that occurs five times more frequently among Hispanic children than others and has a high relapse rate. This type of leukemia, called CRLF2 B-ALL, is characterized by two genetic alterations: a) overexpression of the cytokine receptor, CRLF2, and b) deletion or inactivation of one allele of the Ikaros (IKZF1) tumor suppressor which is strongly associated with relapse. Our overall hypothesis is that combination therapy that selectively targets the pathways that are deregulated in CRLF2 B-ALL (CRLF2 and Ikaros) will produce a superior therapeutic effect and decrease mortality to reduce the health disparity in survival for Hispanic children with ALL. When the CRLF2 receptor is activated by its ligand, TSLP, downstream pathways (JAK/STAT and PI3/AKT/mTOR) that promote leukemia cell survival, proliferation, and chemoresistance are induced through processes normally kept in check by the Ikaros tumor suppressor. Preliminary data from our team show that treatment with the CK2-specific inhibitor, CX-4945, restores Ikaros tumor suppressor function in high-risk B-ALL from Hispanic patients with deletion of one Ikaros allele, exerting a strong in vivo therapeutic effect. Preclinical studies of CRLF2 B-ALL typically use patient-derived xenograft (PDX) models, where primary leukemia cells from patients with CRLF2 B-ALL are injected into immune deficient mice. Our preliminary data show that mouse TSLP does not activate human CRLF2, making the current PDX models suboptimalfor studies of CRLF2 B-ALL. To overcome this obstacle our team engineered immune deficient mice that provide normal human serum levels of human TSLP (+T mice) and generated PDX by injecting these mice with CRLF2 B-ALL cells from Hispanic pediatric patients (+T PDX). Analysis of +T PDX shows CRLF2 activation and gene expression that is more similar to original patient sample than standard PDX. Our preliminary data provide a rationale for novel therapy that targets pathways that are induced by CRLF2 (JAK-STAT5 and PI3K/AKT/mTOR) and by loss of Ikaros tumor suppressor activity using our newly- developed preclinical model for Hispanic CRLF2 B-ALL. To test our hypothesis we will: Aim 1: Establish the in vivo therapeutic efficacy of targeting CRLF2 downstream pathways and their role in CRLF2 B-ALL in Hispanic pediatric patients. Aim 2: Evaluate the in vivo efficacy and mechanisms of combination therapy that restores Ikaros tumor suppressor activity and inhibits the mTOR pathway in Hispanic pediatric CRLF2 B-ALL. The proposed studies use precision medicine approaches (targeting specific pathways and/or functional defects) in context of the health disparity background to develop a novel treatment for CRLF2 B-ALL and reduce childhood cancer health disparities.